Age-related macular degeneration (AMD) is a common, late-onset, and complex trait with multiple risk factors. Concentrating on a region harboring a locus for AMD on 1q25-31, the ARMD1 locus, we tested single nucleotide polymorphisms for association with AMD in two independent case-control populations. Significant association (P = 4.95 x 1010) was identified within the regulation of complement activation locus and centered over a Tyr402His protein polymorphism in the gene encoding complement factor H. Possession of at least one histidine at amino acid 402 increased the risk of AMD 2.7-fold and accounts for 50% of the attributable risk of AMD.